Liver regeneration is a unique biological response in which normally quiescent, differentiated hepatocytes regain proliferate activity. Although the process involves the partially synchronized replication of more than 95% of hepatocytes, replication is strictly regulated and ceases when the liver regains its original mass. Understanding the mechanisms that initiate and regulate liver regeneration is of great scientific and clinical importance. In years 30 to 32 of this MERIT award we have demonstrated that Tumor Necrosis Factor (TNF) one of the main cytokines involved in the initiation of liver regeneration acts both through the NFKB/IL-6/STAT3 pathway that we have previously described, and by transactivating the EGF receptor (EGFR). Transactivation of EGFR involved the release of EGF ligands anchored into the cell membrane by the metalloproteinase TACE, triggering a mitogenic cascade involving ERK1/2 and PKB. We have also shown that one of these ligands, HB-EGF, whose expression is regulated by c-jun/AP1 complexes, plays a key role in linking hepatocyte priming at the start of liver regeneration with cell cycle progression occuring many hours later. This application for extension of the MERIT project period is based on these findings and on other work demonstrating the role of NFicB and SOCS family genes in the initiation of liver regeneration. Placing emphasis on appropriate mouse models and results from ongoing work, we designed experimentswhich address key issues regarding the mechanisms of liver regeneration: 1) the control of hepatocyte survival and proliferation by GSH, 2) LPS receptor signaling as a triggering mechanism for liver regeneration^) the role of SOCS-3 in preventing cytokine toxicity in the regenerating liver,4) the mechanisms by which c-jun/AP-1 complexes control HB-EGF induction and 5) the role of cytokines in regulating differential hepatocyte and progenitor cell responses during liver growth.